Despite the effectiveness of multiple combinations of anti-HIV chemotherapy that was introduced for the management of HIV infection, there are still a number of critical unresolved issues in HIV chemotherapy. It is clear that existing drugs are not always effective primarily due to lack of potency, development of resistant virus, poor pharmacokinetics, lack of penetration into virus reservoirs, drug interactions affecting safety of the drug, oral bioavailability, and poor compliance by HIV infected patients. Based on our knowledge of the molecular biology of HIV, medicinal chemistry know-how, as well as pharmacological approach, our group is uniquely qualified to tackle these challenges. Some of the issues addressed in this proposal are the viral replication in lymphatic systems, targeted drug delivery, dementia and the brain as a viral reservoir, viral resistance and drug combination and interactions. Our proven track record in designing and synthesizing more selective and potent antiviral agents to achieve these goals is well established. During the previous funding period, we developed a promising prodrug, (-)- b-D-2,6-diaminopurine dioxolane (DAPD), which is currently undergoing Phase II clinical trials by Triangle Pharmaceuticals. DAPD is not only a potent anti-HIV agent, but also it has demonstrated a favorable viral resistant profile in vitro as well as in vivo, which is necessary for salvage therapy for AIDS patients. Therefore, DAPD has been designated as a "fast-track" compound by the FDA. In order to further improve the potency, bioavailability, and selective targeted delivery to the lymphatic system and brain, we propose several prodrugs of DAPD. Recently, we also discovered a new class of D-enantiomers of 2'-fluoro-unsaturated nucleosides, including 2'-F-D4A, 2'-F-D4l and 2'F-D4G with potent antiviral activity against mutant viruses. However, these purine nucleosides may be limited as useful agents due to their poor cellular transport. In this application, we proposed to synthesize various prodrugs to improve the potency as well as pharmacokinetic/pharmacodynamic profiles. Very recentiy, we also discovereda potent anti-HIV activity of D4G prodrug (6-cyclopropylamino-D4G), while D4G itself is practically inactive against HIV-1. We plan to conduct various biological evaluation to determine the full potential of this prodrug as a clinical candidate. This approach may be extended to other classes of antiviral agents. In summary, we will continue to study three classes of proposed prodrugs to improve their pharmacokinetics profiles in mice, rats and rhesus monkeys to enhance the efficacy of parent anti-HIV agents. If any prodrugs are found to be promising during these studies, we plan to advance them as clinical candidates.